The purpose of the present proposal is to investigate the hypothesis that female rats will show greater sensitization to the locomotor stimulating effects of cocaine during chronic intermittent treatment. We will investigate two potential mechanisms which might explain this gender difference in sensitization. First, we plan to investigate the possibility that chronic cocaine treatment will produce a greater increment in the ability of cocaine to increase synaptic dopamine in females than in males. Second, we plan to investigate the hypothesis that greater cocaine induced CRF release results in greater ACTH and corticosterone secretion which contributes to the development of sensitization. To test these hypotheses, adult male and female rats will be treated with twice daily cocaine injections (10 mg/kg or 30 mg/kg bid) for varying durations (3,7 or 14 days), and a dose response curve for cocaine-induced locomotor activation and stereotypy will be assessed 7 days after the end of treatment. The role of gonadal steroids will be assessed by evaluating sensitization in intact, gonadectomized and hormonally-replaced males and females. Cocaine effects on synaptic dopamine will be assessed by determining cocaine- induced enhancement of dopamine overflow during electrical stimulation of a superfused slice obtained from corpus striatum or nucleus accumbens after the same treatment. To evaluate the role of HPA axis activation, the ability of cocaine to stimulate ACTH and corticosterone secretion will be determined in male and female rats after a single cocaine dose, and following chronic treatment. In addition, cocaine sensitization will be evaluated in adrenalectomized and dexamethasone-treated males and females. Finally, gender differences in cocaine pharmacokinetics will be assessed to validate that behavioral and neurochemical changes reflect primary gender differences in the brain rather than gender differences in cocaine disposition. The purpose of these studies is to investigate possible biological factors which might lead to differential effects of stimulants in males and females. This information could provide new insight into the consequences of chronic stimulant exposure, and possible differences in therapeutic strategies used in men an women.